3-(Acetylamino)propylsulfonic acid, also referred to as N-acetylhomotaurine or acamprosate:
is a derivative of homotaurine, a naturally occurring structural analog of γ-aminobutyric acid (GABA) that appears to affect multiple receptors in the central nervous system (CNS). As an antiglutamatergic agent, acamprosate is believed to exert a neuropharmacological effect as an antagonist of N-methyl-D-aspartate (NMDA) receptors. The mechanism of action is believed to include blocking of the Ca2+ channel to slow Ca2+ influx and reduce the expression of c-fos, leading to changes in messenger RNA transcription and the concomitant modification to the subunit composition of NMDA receptors in selected brain regions (Zornoza et al., CNS Drug Reviews, 2003, 9(4), 359-374; and Rammes et al., Neuropharmacology 2001, 40, 749-760). There is also evidence that acamprosate may interact with excitatory glutamatergic neurotransmission in general, and as an antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5) in particular (De Witte et al., CNS Drugs 2005, 19(6), 517-37). The glutamatergic mechanism of action of acamprosate may explain the effects of acamprosate on alcohol dependence, and suggests other therapeutic activities, such as in neuroprotection.
A number of issued patents and published patent applications relate to the use of acamprosate as a medicament. For example, U.S. Pat. Nos. 6,391,922 and 6,689,816 disclose a novel treatment for neuropsychiatric disorders, including anxiety disorders, mood disorders, psychotic disorders, somatoform disorders, and neuropsychiatric symptoms resulting from movement disorders. The treatment utilizes any agent that simultaneously act as NMDA-type glutamate receptor antagonists and GABA-A receptor agonists. Preferably, these two activities are characteristic of a single agent, for example, acamprosate (calcium N-acetylhomotaurinate). Alternatively, separate agents having these activities can be combined as a compound or mixture and thereby administered together. The invention also provides for a third agent that acts as a non-competitive NMDA-receptor blocking agent or ion channel blocker that augments the effect of the primary treatment. A particularly preferred ion channel blocking agent is magnesium.
U.S. Pat. No. 7,745,493 discloses a novel treatment for movement disorders, including tardive dyskinesia, tic disorders, Tourette's syndrome, and blepharospasm, and other focal dystonias. The treatment utilizes agents that simultaneously act as NMDA-type glutamate receptor antagonists and GABA-A receptor agonists. Preferably, these two activities are characteristic of a single agent, for example acamprosate. Alternatively, separate agents having these activities can be combined and administered together. The invention also provides a third agent that acts as a non-competitive NMDA-receptor blocking agent or ion channel blocker that augments the effect of the primary treatment. A particularly preferred ion channel blocking agent is magnesium. Alternatively, magnesium can be administered alone for prevention and treatment of movement disorders.
U.S. Pat. No. 8,865,769 discloses combinations and methods for the treatment of neurological disorders related to glutamate excitotoxicity and Amyloid 3 toxicity. More specifically, the invention relates to novel combinatorial therapies of Multiple Sclerosis, Alzheimer's disease, Alzheimer's disease related disorder, Amyotrophic Lateral Sclerosis, Parkinson's disease, Huntington's disease, neuropathic pain, alcoholic neuropathy, alcoholism or alcohol withdrawal, or spinal cord injury, based on Baclofen and Acamprosate combination.
Published US Patent application no. 2011/0294879 discloses methods of treating fragile X syndrome, fragile X-associated tremor/ataxia syndrome, Down's syndrome and/or, comprising administering a prodrug of acamprosate to a subject suffering therefrom.
WO 2010093859 A1 relates to subjects who were diagnosed with either comorbid or idiopathic autism and fragile x syndrome and treated with acamprosate. Patients generally showed marked improvements in primary outcomes as assessed using, for example, standard clinic measures for functionality including the Clinical Global Impressions Improvement (CGI-I) and the Clinical Global Impressions Severity (CGI-S) scales.
A number of issued patents and published patent applications relate to forms and formulations of acamprosate. For example, U.S. Pat. No. 6,426,087 discloses an orally administrable galenic form allowing improved absorption by the transmembrane or paracellular route in the gastrointestinal tract of active ingredients which are hydrophilic or ionizable in physiol. media, comprising at least one such active ingredient, an absorption-promoting agent having an HLB>8, the absorption-promoting agent consisting of one or more lipid substances chosen from: polysorbates; polyoxyethylene ethers; esters of polyoxyethylene and fatty acids; fatty acids; fatty alcs.; bile acids and their salts with pharmaceutically acceptable cations; esters of C1-C6 alkanol with fatty acids; esters of polyol with fatty acids, the polyol comprising from 2 to 6 hydroxyl functional groups; and polyglycolyzed glycerides; in combination with one or more pharmaceutically acceptable excipients, the pharmaceutical forms comprising captopril being excluded. A controlled-release tablet contained (1) cores contg. calcium acamprosate 50, Gelucire 44/14 10, Compritol 10, microcryst. cellulose 19, Povidone 10, and Mg stearate 1% and (2) a film-coating compn. contg. HPMC 64, PEG-4000 15, and talc 21%.
U.S. Pat. No. 6,512,009 discloses a pharmaceutical composition for the treatment of alcohol and drug dependence, comprising a therapeutically effective amount of a combination of: (i) an opioid antagonist; and (ii) a NMDA receptor complex modulator. A pharmaceutical kit is also provided, comprising these two substances. The opioid antagonist can, for example, be naltrexone and the NMDA receptor complex modulator can be a spermidine site modulator such as acamprosate.
U.S. Pat. No. 7,994,218 discloses pantoic acid ester neopentyl sulfonyl ester prodrugs of acamprosate, pharmaceutical compositions comprising such prodrugs, and methods of using such prodrugs and compositions thereof for treating diseases. In particular, acamprosate prodrugs exhibiting enhanced oral bioavailability and methods of using acamprosate prodrugs to treat neurodegenerative disorders, psychotic disorders, mood disorders, anxiety disorders, somatoform disorders, movement disorders, substance abuse disorders, binge eating disorder, cortical spreading depression related disorders, tinnitus, sleeping disorders, multiple sclerosis, and pain are disclosed.
U.S. Pat. No. 8,268,352 discloses a novel modified release dosage form comprising of a high solubility active ingredient, which utilizes dual retard technique to effectively reduce the quantity of release controlling agents. The dosage form can optionally comprise another active ingredient as an immediate release form or modified release form. The invention also relates to a process for preparing the said formulation.
U.S. Pat. No. 9,000,046 discloses gastric retentive dosage forms for sustained release of acamprosate which may allow once- or twice-daily dosing for both acute and long-term treatment of a disorder including alcohol dependence, tinnitus, sleep apnea, Parkinson's disease, levodopa-induced dyskinesias in Parkinson's disease, Alzheimer's disease, Huntington's disease, Amyotrophic lateral sclerosis, Cortical spreading depression, migraine, schizophrenia, anxiety, tardive dyskinesia, spasticity, multiple sclerosis, various types pain, or binge eating. Methods of treatment using the dosage forms and methods of making the dosage forms are also described.
Published US Patent application no. 2011/0182953 discloses a new polymorphic form of calcium acetyl-homotaurinate, designated as form B, and processes for the preparation of said form B and of the known crystalline form.
Published US patent application no. 2013/0310456 discloses embodiments generally related to acamprosate formulations, methods of use of the formulations, methods of using the formulations in combination with at least one other medication, and combination products and compositions comprising the formulations and at least one other medication, such as neuroleptic (antipsychotic) and/or antidepressant drugs.
Acamprosate is a polar molecule that lacks the requisite physicochemical characteristics for effective passive permeability across cellular membranes. As a consequence, the oral bioavailability of acamprosate in humans is only about 11%, and poor absorption of the drug from the GI tract likely contributes to its limited tolerability. One consequence is that a relatively large tablet has been required to achieve a therapeutic effect.
Acamprosate calcium, marketed as Campral® by Forest Pharma, was first approved by the FDA in 2004. Campral® is indicated for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation. Campral® is supplied as an enteric-coated tablet for oral administration. Each Campral® tablet contains acamprosate calcium 333 mg, equivalent to 300 mg of acamprosate. Inactive ingredients in Campral® tablets include: crospovidone, microcrystalline cellulose, magnesium silicate, sodium starch glycolate, colloidal anhydrous silica, magnesium stearate, talc, propylene glycol and Eudragit® L 30 D or equivalent. Sulfites were used in the synthesis of the drug substance and traces of residual sulfites may be present in the drug product. Campral® 333 mg tablets are enteric-coated, white, round, biconvex tablets, identified with “333” debossed on one side. The recommended dose of Campral® is two 333 mg tablets (each dose should total 666 mg) taken three times daily. A lower dose may be effective in some patients. Although dosing may be done without regard to meals, dosing with meals was employed during clinical trials and is suggested in those patients who regularly eat three meals daily. As an enteric-coated tablet, any disruption of the coating allows for immediate dissolution of the tablet before moving through the upper digestive tract and into the lower digestive tract for absorption. When the pill's enteric-coating is broken (i.e. chewed or cut), then an adverse reaction is encouraged and GI distress (diarrhea nausea and vomiting) increases.
The current formulation of Campral® is a solid formed, 333 mg round tablet and is a 10 mm in size. Also known as AOTAL in Europe, the drug is available in 400 mg and 800 mg tablets. The size of the tablet presents a challenge for both pediatric and adult patients. The FDA issued draft guidance on size, shape and other physical attributes of generic tablets and capsules which outlines the difficulties swallowing tablets and capsules for many individuals and can lead to a variety of adverse events and patient noncompliance with treatment regimens. (www.fda.gov/downloads/drugs/guidancecomplianceregulatory information/guidances/ucm377938.pdf) The guidance estimates over 16 million people in the U.S. have some difficulty swallowing a tablet or capsule. The size and shape of the tablets can affect the transit of the product through the pharynx and esophagus and may directly affect the patient's ability to swallow a product. This can lead to disintegration of the product in the esophagus and the potential for ulceration, stricture or perforation as well as other adverse events like pain, gagging, choking and aspiration. The studies presented by the FDA suggest that tablets larger than 8 mm in diameter are associated with increases in patient complaints and difficulties and increased esophageal transit time.
Consistent with its activity as a functional glutamaterigic antagonist, a clinical study of Campral® (acamprosate calcium) in subjects with Fragile X Syndrome (FXS) and comorbid autistic disorder demonstrated significant symptomatic improvements as assessed by the investigators' Clinical Global Impression (CGI-I), with improvements in communication and social interaction skills being particularly noteworthy (Erickson et al, J. Autism Dev. Disord. 2010). Gastrointestinal distress (nausea and vomiting) are commonly observed side effects in subjects receiving acamprosate, and adverse GI events were observed in the majority of Fragile X subjects treated in this study.
A published study conducted by Bailey (Bailey D. B., et. al. Medication Utilization for Targeted Symptoms in Children and Adults with Fragile X Syndrome: US Survey. J Dev Behav Pediatr. 2012 33:62-69) further demonstrated that between 40%-90% of pediatric patients with Fragile X Syndrome (n=1,361 FXS patients) had significant difficulty swallowing a whole solid pill. While pill swallowing remains a difficult exercise for a majority pediatric patients, it does improve with age and training. However, this challenge still remains for at least 20% of Fragile X Syndrome adults, elderly patients or populations with swallowing difficulties. This data is consistent with the clinical experience by Dr. Erickson and has been a barrier to recruiting patients for open-label pilot studies with Campral®.
There is still a long-felt and unmet need for new oral formulations of acamprosate which do not induce gastrointestinal problems to treat patients who are unable or unlikely to swallow tablet or capsule formulations of the drug.